Genome-wide Consequences of Deleting Any Single Gene

The loss of a gene puts pressure on an organism to compensate, which leads to mutation in one or more different genes elsewhere in its genome, researchers say.

The discovery, made in yeast, is likely applicable to human genetics because of the way DNA is conserved across species. The findings could change the way genetic analysis is done in cancer and other areas of research, the scientists say.

Published in Molecular Cell, the results add to the evidence that genomes, the sum total of species’ genes, are like supremely intricate machines: removal of a single, tiny part stresses the whole mechanism and might cause another part to warp elsewhere to fill in for the missing piece.

After deletion of gene B from an organism’s genome, stability can be maintained only through a compensatory secondary mutation in gene A. (Credit: Xinchen Teng/JHU, courtesy of Molecular Cell)

Says J. Marie Hardwick, professor of molecular microbiology and immunology at the Johns Hopkins Bloomberg School of Public Health and of pharmacology and molecular sciences at the university’s School of Medicine:

“The deletion of any given gene usually results in one, or sometimes two, specific genes being ‘warped’ in response.

Pairing the originally deleted gene with the gene that was secondarily mutated gave us a list of gene interactions that were largely unknown before.”

Hardwick says the findings should prompt researchers to be even more careful in genetic analyses; otherwise, they might attribute a phenomenon to a gene they mutated, when it is actually caused by a secondary mutation.

“We had been thinking of cancer as progressing from an initial mutation in a tumor-suppressor gene, followed by additional mutations that help the cancer thrive,” says Hardwick.

“Our work provides hard evidence that a single one of those ‘additional mutations’ might come first and actively provoke the mutations seen in tumor-suppressor genes. We hope that our findings in yeast will help to identify these ‘first’ mutations in tumors.”

The beauty of working with yeast, Hardwick says, is that it is easy to delete, or “knock out,” any given gene. Her team started with a readily available collection of thousands of different yeast strains, each with a different gene knockout.

Hardwick believes that “essentially any gene, when mutated, has the power to alter other genes in the genome.” Deleting the first gene seems to cause a biological imbalance that is sufficient to provoke additional adaptive genetic changes, she explains.

Abstract

“Loss or duplication of chromosome segments can lead to further genomic changes associated with cancer. However, it is not known whether only a select subset of genes is responsible for driving further changes. To determine whether perturbation of any given gene in a genome suffices to drive subsequent genetic changes, we analyzed the yeast knockout collection for secondary mutations of functional consequence. Unlike wild-type, most gene knockout strains were found to have one additional mutant gene affecting nutrient responses and/or heat-stress-induced cell death. Moreover, independent knockouts of the same gene often evolved mutations in the same secondary gene. Genome sequencing identified acquired mutations in several human tumor suppressor homologs. Thus, mutation of any single gene may cause a genomic imbalance, with consequences sufficient to drive adaptive genetic changes. This complicates genetic analyses but is a logical consequence of losing a functional unit originally acquired under pressure during evolution.”